Time-dependent neuroprotective effects of YL-IPA08 in repetitive mild traumatic brain injury associated with changes in Caprin1/SHH signaling.

Abstract

Repetitive mild traumatic brain injury (rmTBI) triggers chronic neuroinflammation, oxidative stress, and synaptic dysfunction, resulting in long-term cognitive and emotional impairments. Effective pharmacological interventions remain scarce. Caprin1, a stress-responsive RNA-binding protein, regulates stress granules (SGs) dynamics and mRNA translation, while Sonic Hedgehog (SHH) signaling mediates neurogenesis and glial reactivity. YL-IPA08, a potent translocator protein (TSPO) ligand, exhibits neuroprotective efficacy in several neurological models, yet its temporal effects in rmTBI are unknown. Using a murine thinned-skull rmTBI model, we compared acute (YL-AcT, 0-3 days post-injury) and intermediate-phase (YL-IntT, 8-42 days) YL-IPA08 treatment paradigms. YL-AcT enhanced Caprin1/SHH co-expression, increased Caprin1-associated cytoplasmic granules consistent with SGs-like structures, and elevated DCXimmature neuronal signals in the hippocampal DG without behavioral improvement, suggesting persistent cellular stress responses. In contrast, YL-IntT significantly improved motor, affective, and cognitive performance, reduced Caprin1 and SHH immunoreactivity, decreased the abundance of Caprin1-associated cytoplasmic granules, and partially restored hippocampal cytoarchitecture. YL-IntT also suppressed SHH/C3 co-expression, suggesting attenuation of neurotoxic astrocytic activation. TSPO expression showed dynamic, cell type-specific modulation across astrocytes and other cell populations, supporting a phase-dependent neuroprotective mechanism. Collectively, these findings suggest that YL-IPA08 exerts timing (treatment-window)-dependent neuroprotective effects that are temporally associated with alterations in Caprin1 and SHH signaling proteins, Caprin1-associated stress-responsive granule dynamics, and changes in TSPO expression patterns, potentially contributing to neuron-glia homeostasis under conditions of TSPO modulation. However, the present findings reflect associative relationships, and further studies will be required to determine the causal mechanisms linking TSPO modulation, Caprin1/SHH signaling, and functional recovery following rmTBI.